Ionization probe assemblies

ABSTRACT

The invention relates generally to sample ionization, and provides ionization probe assemblies, systems, computer program products, and methods useful for this purpose.

The present application claims priority to U.S. Provisional PatentApplication Ser. No. 61/152,214, filed Feb. 12, 2009, the entiredisclosure of which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates generally to sample ionization, and providesionization probe assemblies, systems, computer program products, andmethods useful for this purpose.

BACKGROUND OF THE INVENTION

Mass spectrometry (MS) is an analytical technique that can be used todetermine the chemical composition of a sample, and to supply dataimportant to assigning the chemical structures of the components. Itdoes so by ionizing the components to generate charged molecules andmolecule fragments, and then measuring their mass-to-charge ratios. Inan MS procedure, a sample is introduced into the MS instrument,typically by a pump or syringe, and its components undergo ionizationthrough one of a variety of mechanisms resulting in the formation ofcharged particles. The mass-to-charge ratio of the particles can then becalculated based on behavior of the ions as they pass through electricand magnetic fields generated by the MS instrument.

Electrospray ionization (ESI) is one technique used in MS to produceions. It is especially useful in producing ions from macromoleculesbecause it overcomes the propensity of these molecules to fragment whenionized. In electrospray ionization, a liquid is pushed through a verysmall, charged and usually metal, capillary. This liquid contains thesubstance to be studied, the analyte, dissolved in a large amount ofsolvent, which is usually much more volatile than the analyte. Volatileacids, bases or buffers are often added to this solution too. Theanalyte exists as an ion in solution either in its anion or cation form.Because like charges repel, the liquid pushes itself out of thecapillary and forms an aerosol. An uncharged carrier gas such asnitrogen is sometimes used to help nebulize the liquid and to helpevaporate the neutral solvent in the droplets. As the solventevaporates, the analyte molecules are forced closer together, repel eachother and break up the droplets. This process is called Coulombicfission because it is driven by repulsive Coulombic forces betweencharged molecules. The process repeats until the analyte is free ofsolvent and is a lone ion.

As MS usage and applications continue to increase, there continues to bea need for improved MS systems and improved components for use in MSsystems and methods.

SUMMARY OF THE INVENTION

The present invention provides ionization probe assemblies that areuseful in spraying and ionizing sample materials. Typically, theionization probe assemblies are configured to substantially continuouslyintroduce sample materials into ion source housings of molecular massmeasurement systems via multiple probes that are individually configuredto discontinuously spray or otherwise introduce sample materials intothe ion source housings. In some embodiments, for example, probes of theionization probe assemblies are configured to duty cycle between sprayand rinse positions that are substantially electrically isolated fromone another. In addition to ionization probe assemblies, the inventionalso provides related molecular mass measurement systems, computerprogram products, and methods.

In one aspect, the invention provides an ionization probe assembly thatincludes at least one probe mounting structure and at least one probethat is movably coupled to the probe mounting structure. The probe isconfigured to discontinuously introduce sample aliquots into an ionsource housing. In addition, the ionization probe assembly also includesat least one probe conveyance mechanism operably connected to the probe.The probe conveyance mechanism is configured to convey the probe betweenat least a first position and at least a second position. The firstposition is substantially electrically isolated from the secondposition. In some embodiments, an electrospray ion source housingincludes the ionization probe assembly. In these embodiments, a massspectrometer typically includes the electrospray ion source housing. Incertain embodiments, at least one cavity is disposed in or proximal tothe probe mounting structure. The cavity typically comprises the secondposition. In some of these embodiments, the cavity fluidly communicateswith at least one outlet. Typically, the ionization probe assemblyincludes at least two probes that are each movably coupled to the probemounting structure. In these embodiments, the probes are generallyindependently movably coupled to the probe mounting structure. In someembodiments, the ionization probe assembly comprises at least onewide-bore probe. In some embodiments, the probe mounting structurecomprises a removable cartridge. In some embodiments, the removablecartridge is spring-loaded. In some embodiments, the probe mountingstructure is configured to accept removable cartridges from a variety ofcommercial instruments. In some embodiments, the ionization probeassembly comprises one or more nebulizer gas lines configured to delivergas from a nebulizer gas source to at least one probe. In someembodiments, one or more nebulizer gas lines comprise a thermalmodulator to heat gas within one or more nebulizer gas lines.

The probe mounting structures include various embodiments. In certainembodiments, for example, the probe mounting structure includes at leastone view port. In some embodiments, at least one cover operablyconnected to the probe mounting structure. In certain embodiments, theprobe mounting structure comprises an ion source housing back plate thatis configured to operably connect to an ion source housing. In theseembodiments, the ion source housing back plate typically comprises atleast one alignment feature that is structured to align the ion sourcehousing back plate relative to the ion source housing when the ionsource housing back plate operably connects to the ion source housing.In some embodiments, at least a first mounting component is operablyconnected to the probe mounting structure. The first mounting componentis configured to engage at least a second mounting component that isoperably connected to an ion source housing when the probe mountingstructure is mounted on the ion source housing. Typically, the first andsecond mounting components comprise hinge and/or latch components. Incertain embodiments, the probe mounting structure comprises an ionsource housing. In some of these embodiments, the ion source housingcomprises at least one view port.

Typically, at least one channel is disposed through a length of theprobe. In addition, the probe generally comprises at least one sprayerneedle that fluidly communicates with the channel. In some embodiments,at least one nebulizer gas source and/or nebulizer gas sheath fluidlycommunicates with the channel.

In some embodiments, the ionization probe assembly includes at least onethermal modulator operably connected to the probe. The thermal modulatoris typically configured to modulate a temperature of the probe. Incertain embodiments, for example, the thermal modulator comprises anebulizer gas heater. Typically, at least one controller circuit boardoperably connected to the thermal modulator.

In certain embodiments, the ionization probe assembly includes at leasttwo probes independently that are movably coupled to the probe mountingstructure. Typically, each probe is movably coupled to the probemounting structure via a pivot mechanism. In some embodiments, the probeconveyance mechanism comprises at least one motor operably connected toat least one of the pivot mechanisms via a pulley and belt driveassembly. Optionally, each probe is configured to move between a sprayposition and a rinse position in which the spray position issubstantially electrically isolated from the rinse position. In certainembodiments, at least one cavity is disposed in or proximal to the probemounting structure. The cavity generally comprises at least one of therinse positions. In these embodiments, the cavity typically fluidlycommunicates with at least one outlet.

In some embodiments, the probe is movably coupled to the probe mountingstructure via a slide mechanism. Typically, the slide mechanismcomprises at least two probes. In some of these embodiments, the probesare substantially fixedly coupled to the slide mechanism. In certainembodiments, the first position comprises a spray position and thesecond position comprises at least first and second rinse positions thatare each substantially electrically isolated from the spray position.Typically, when a first probe is in the spray position, a second probeis in the second rinse position, and when the second probe is in thespray position, the first probe is in the first rinse position. In someof these embodiments, the slide mechanism comprises a probe supportplate coupled to the probe mounting structure via a linear slide, andthe probe is mounted on the probe support plate. In certain embodiments,the probe conveyance mechanism comprises a dual acting pneumaticcylinder operably connected to the probe mounting structure and to theprobe support plate.

In another aspect, the invention provides an ionization probe assemblythat includes at least one ion source housing back plate that comprisesone or more surfaces that define at least one spray orifice. The ionsource housing back plate is configured to operably connect to an ionsource housing. The ionization probe assembly also includes at least onerinse cavity that is at least partially disposed within the ion sourcehousing back plate in which the rinse cavity communicates with the sprayorifice via at least one opening. Typically, the rinse cavity fluidlycommunicates with at least one outlet. In addition, the ionization probeassembly also includes at least one probe support structure coupled tothe ion source housing back plate via at least one linear slide, and atleast one probe substantially fixedly mounted on the probe supportstructure. The ionization probe assembly also includes at least oneprobe conveyance mechanism operably connected to the probe supportstructure. The probe conveyance mechanism is configured to selectivelyconvey the probe support structure such that the probe slides betweenthe spray orifice and the rinse cavity through the opening.

In another aspect, the invention provides an ionization probe assemblythat includes at least one ion source housing back plate that comprisesone or more surfaces that define at least one spray orifice. The ionsource housing back plate is configured to operably connect to an ionsource housing. The ionization probe assembly also includes at least onerinse cavity that is at least partially disposed within the ion sourcehousing back plate in which the rinse cavity communicates with the sprayorifice via at least one opening, and at least one probe movably coupledto the ion source housing back plate via at least one pivot mechanism.In addition, the ionization probe assembly also includes at least oneprobe conveyance mechanism that comprises at least one motor operablyconnected to the pivot mechanism via a pulley and belt drive assembly.The probe conveyance mechanism is configured to selectively convey theprobe between the spray orifice and the rinse cavity through theopening.

In another aspect, the invention provides a molecular mass measurementsystem. The system includes at least one mass spectrometer thatcomprises at least one ion source housing, and at least one ionizationprobe assembly operably connected to the ion source housing. Theionization probe assembly comprises: at least one probe mountingstructure; at least one probe that comprises at least one inlet and atleast one outlet in which the inlet fluidly communicates with theoutlet, the probe is movably coupled to the probe mounting structure,which probe is configured to discontinuously introduce sample aliquotsinto the ion source housing; and at least one probe conveyance mechanismoperably connected to the probe, which probe conveyance mechanism isconfigured to convey the probe between a spray position and a rinseposition in which the spray position is substantially electricallyisolated from the rinse position. The system also includes at least onesample source in fluid communication with the inlet of the probe, and atleast one rinse fluid source in fluid communication with the inlet ofthe probe. In addition, the system also includes at least one controlleroperably connected at least to the ionization probe assembly. Thecontroller is configured to selectively direct the ionization probeassembly to: (a) convey the probe from the rinse position to the sprayposition; (b) spray at least one sample aliquot into the ion sourcehousing from the sample source when the probe is in the spray position;(c) convey the probe from the spray position to the rinse position; and(d) rinse the probe with rinse fluid from the rinse fluid source whenthe probe is in the rinse position. In some embodiments, the systemincludes at least one additional system component selected from, e.g.,at least one nucleic acid amplification component; at least one samplepreparation component; at least one microplate handling component; atleast one mixing station; at least one material transfer component; atleast one sample processing component; at least one database; and thelike.

In another aspect, the invention provides a computer program productthat includes a computer readable medium having one or more logicinstructions for directing an ionization probe assembly of a molecularmass measurement system to: (a) convey a first probe from a first rinseposition to a first spray position of the molecular mass measurementsystem, wherein the first rinse position and the first spray positionare substantially electrically isolated from one another; (b) convey asecond probe from a second spray position to a second rinse position ofthe molecular mass measurement system, wherein the second spray positionand the second rinse position are substantially electrically isolatedfrom one another; (c) spray at least a first sample aliquot into an ionsource housing of the molecular mass measurement system via the firstprobe when the first probe is in the first spray position; (d) rinse thesecond probe when the second probe is in the second rinse position; (e)convey the first probe from the first spray position to the first rinseposition; (f) convey the second probe from the second rinse position tothe second spray position; (g) spray at least a second sample aliquotinto the ion source housing of the molecular mass measurement system viathe second probe when the second probe is in the second spray position;and, (h) rinse the first probe when the first probe is in the firstrinse position. In some embodiments, the computer program productincludes at least one logic instruction for directing the ionizationprobe assembly of the molecular mass measurement system to modulate atemperature of the first probe and/or second probe using at least onethermal modulator operably connected to the first probe and/or secondprobe. In certain embodiments, the logic instructions are configured todirect the ionization probe assembly to execute (a) substantiallysimultaneously with (b), (c) substantially simultaneously with (d), (e)substantially simultaneously with (f), and/or (g) substantiallysimultaneously with (h). Typically, a controller of the molecular massmeasurement system comprises the logic instructions.

In another aspect, the invention provides a method of spraying samplealiquots into an ion source housing of a molecular mass measurementsystem. The method includes (a) conveying a first probe from a firstrinse position to a first spray position of the molecular massmeasurement system in which the first rinse position and the first sprayposition are substantially electrically isolated from one another andwherein the first spray position is in fluid communication with the ionsource housing; and (b) conveying a second probe from a second sprayposition to a second rinse position of the molecular mass measurementsystem, wherein the second spray position and the second rinse positionare substantially electrically isolated from one another. The methodalso includes (c) spraying at least a first sample aliquot into the ionsource housing via the first probe when the first probe is in the firstspray position; (d) rinsing the second probe when the second probe is inthe second rinse position; and (e) conveying the first probe from thefirst spray position to the first rinse position. In addition, themethod also includes (f) conveying the second probe from the secondrinse position to the second spray position in which the second sprayposition is in fluid communication with the ion source housing; (g)spraying at least a second sample aliquot into the ion source housing ofthe molecular mass measurement system via the second probe when thesecond probe is in the second spray position; and (h) rinsing the firstprobe when the first probe is in the first rinse position, therebyspraying the sample aliquots into the ion source housing of themolecular mass measurement system. In certain embodiments, the methodincludes performing (a) substantially simultaneously with (b), (c)substantially simultaneously with (d), (e) substantially simultaneouslywith (f), and/or (g) substantially simultaneously with (h).

In some embodiments, the method includes modulating a temperature of thefirst probe and/or second probe using at least one thermal modulatoroperably connected to the first probe and/or second probe. Typically,the method includes ionizing the first sample aliquot and the secondsample aliquot when the first sample aliquot and the second samplealiquot are sprayed into the ion source housing. The method alsogenerally includes measuring a molecular mass of at least one componentof the first sample aliquot and/or the second sample aliquot using themolecular mass measurement system. In some embodiments, the component ofthe first sample aliquot and/or the second sample aliquot comprises atleast one nucleic acid molecule. In these embodiments, the methodgenerally comprises determining a base composition of the nucleic acidmolecule from the molecular mass of the nucleic acid molecule. Incertain of these embodiments, the method includes correlating the basecomposition of the nucleic acid molecule with an identity or property ofthe nucleic acid molecule.

BRIEF DESCRIPTION OF THE DRAWINGS

The description provided herein is better understood when read inconjunction with the accompanying drawings which are included by way ofexample and not by way of limitation. It will be understood that likereference numerals identify like components throughout the drawings,unless the context indicates otherwise. It will also be understood thatsome or all of the figures may be schematic representations for purposesof illustration and do not necessarily depict the actual relative sizesor locations of the elements shown.

FIG. 1 schematically shows an exemplary dual sprayer mounted on a timeof flight spectrometer (TOF).

FIG. 2 schematically shows an exemplary dual sprayer mounted on a TOFchamber.

FIG. 3 schematically shows an exemplary dual sprayer with two probesmounted on an ion source housing.

FIG. 4 a schematically shows an exemplary dual sprayer with the proximalprobe in a sprayer position.

FIG. 4 b schematically shows an exemplary dual sprayer with the proximalprobe in a rinse position.

FIG. 5 schematically shows an exemplary cover covering a dual sprayermounted on an ion source housing.

FIG. 6 a schematically shows an exemplary dual sprayer with a mountingstructure mounted on an ion source housing.

FIG. 6 b schematically shows an exemplary dual sprayer with a mountingstructure mounted on an alternative ion source housing.

FIG. 7 schematically shows an exemplary dual sprayer probe mounted on adual sprayer.

FIG. 8 schematically shows an exemplary dual sprayer with two probesmounted on a sliding mechanism.

FIG. 9 a schematically shows an exemplary dual sprayer having a firstprobe in a first position and a second probe in a second position.

FIG. 9 b schematically shows an exemplary dual sprayer having a firstprobe in a second position and a second probe in a first position.

FIG. 10 schematically shows an exemplary wide-bore dual sprayer mountedon a time of flight spectrometer (TOF).

FIG. 11 schematically shows an exemplary wide-bore dual sprayer mountedon a TOF chamber.

FIG. 12 schematically shows an exemplary wide-bore dual sprayer with twoprobes mounted on an ion source housing.

FIG. 13 a schematically shows an exemplary wide-bore dual sprayer withthe proximal probe in a sprayer position.

FIG. 13 b schematically shows an exemplary wide-bore dual sprayer withthe proximal probe in a rinse position.

FIG. 14 schematically shows an exemplary wide-bore cover covering awide-bore dual sprayer mounted on an ion source housing.

FIG. 15 schematically shows a rear-view of an exemplary wide-bore dualsprayer with two probes mounted on an ion source housing.

FIG. 16 schematically shows a side-view of an exemplary wide-bore dualsprayer with two probes mounted on an ion source housing.

FIG. 17 schematically shows a front-view of an exemplary wide-bore dualsprayer with two probes mounted on an ion source housing.

FIG. 18 schematically shows a top-view of an exemplary wide-bore dualsprayer with two probes mounted on an ion source housing.

DETAILED DESCRIPTION I. Definitions

Before describing the invention in detail, it is to be understood thatthis invention is not limited to particular cartridges, mixing stations,systems, kits, or methods, which can vary. As used in this specificationand the appended claims, the singular forms “a,” “an,” and “the” alsoinclude plural referents unless the context clearly provides otherwise.Thus, for example, reference to “a cartridge” includes a combination oftwo or more cartridge. It is also to be understood that the terminologyused herein is for the purpose of describing particular embodimentsonly, and is not intended to be limiting. Further, unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this invention pertains. In describing and claiming the invention,the following terminology, and grammatical variants thereof, will beused in accordance with the definitions set forth below.

The term “communicate” refers to the direct or indirect transfer ortransmission, and/or capability of directly or indirectly transferringor transmitting, something at least from one thing to another thing.Objects “fluidly communicate” with one another when fluidic material is,or is capable of being, transferred from one object to another.

The term “material” refers to something comprising or consisting ofmatter. The term “fluidic material” refers to material (such as, aliquid or a gas) that tends to flow or conform to the outline of itscontainer.

The term “molecular mass” refers to the mass of a compound as determinedusing mass spectrometry, for example, ESI-MS. Herein, the compound ispreferably a nucleic acid. In some embodiments, the nucleic acid is adouble stranded nucleic acid (e.g., a double stranded DNA nucleic acid).In some embodiments, the nucleic acid is an amplicon. When the nucleicacid is double stranded the molecular mass is determined for bothstrands. In one embodiment, the strands may be separated beforeintroduction into the mass spectrometer, or the strands may be separatedby the mass spectrometer (for example, electro-spray ionization willseparate the hybridized strands). The molecular mass of each strand ismeasured by the mass spectrometer.

The term “system” refers a group of objects and/or devices that form anetwork for performing a desired objective.

II. Introduction

The invention relates to ionization probe assemblies that are useful inspraying and ionizing sample materials, and in various embodimentsprovides individual sub-components, software, control components, andrelated methods employing the assemblies. In some embodiments, theionization probe assemblies are configured to substantially continuouslyintroduce sample materials into ion source housings of molecular massmeasurement systems via multiple probes that are individually configuredto discontinuously spray or otherwise introduce sample materials intothe ion source housings. In some embodiments, for example, probes of theionization probe assemblies are configured to duty cycle between sprayand rinse positions that are substantially electrically isolated fromone another.

III. Example Systems A. Dual Sprayer

FIG. 1 shows a representative time of flight spectrometer (TOF) 100having an exemplary dual sprayer 110 mounted thereon. FIG. 2 shows thedual sprayer 110 mounted on a TOF chamber 101, showing the chamberdetached from the TOF. FIG. 3 shows the dual sprayer 110 separate fromthe TOF or the TOF chamber. The dual sprayer 110 comprises an ionizationprobe assembly that includes at least one probe mounting structure 120and two probes 130 that are movably coupled to the probe mountingstructure 120. Any number of configurations may be used to movablycouple the probes 130 to the probe mounting structure 120, so long asthe desired position and movement of the probes 130 is provided. Theprobes 130 are configured to discontinuously introduce sample aliquotsinto the TOF chamber 101 (not shown in FIG. 3). Samples are introducedinto a probe via a probe opening 140. The probe 130 may be mounted on aprobe conveyance mechanism 150, operably connected to the probe. Theprobe conveyance mechanism 150 is configured to convey the probe betweenat least a first position and at least a second position. As shown inFIG. 3, the two probes 130 are configured to pivot around an axis 160permitting movement from the first position to the second position. Thefirst position is substantially electrically isolated from the secondposition. The dual sprayer 110 may comprise least two independent probes130 that are movably coupled to the probe mounting structure 120. Eachprobe is movably coupled to the probe mounting structure 120 via a pivotmechanism 125. The probe conveyance mechanism 150 comprises a motor 151operably connected to a pivot mechanisms 125 via belt drive 152.

FIGS. 4 a and 4 b show a side view of the dual sprayer 110. In FIG. 4 a,the front-most probe 130 is shown in the second position, or “spray”position. In FIG. 4 b the front-most probe 130 is shown in the firstposition, or “rinse” position. A cavity is disposed in or proximal tothe probe mounting structure 120 to permit movement of the probe 130into the second position. The cavity typically comprises the secondposition. In some of these embodiments, the cavity fluidly communicateswith at least one outlet. The probes 130 are generally independentlymovably coupled to the probe mounting structure 120. In certainembodiments, the probe mounting structure 120 includes at least one viewport 123 (FIG. 8) to permit viewing of the probes. The one or more viewports 123 (FIG. 8) may comprise a glass, plastic, ceramic or othertransparent material to provide a window located on any desired regionof the mounting structure 120.

FIG. 5 shows a dual sprayer 110 comprising a cover 200 affixed to andcovering the mounting structure 120. The cover 200 may be made of anydesired material and can substantially or partially cover the mountingstructure 120. The cover 200 may be affixed to the mounting structuresby screws, bolts, clamps, pins, or via any other connection means. Thecover may comprise one or more slots or openings 210 to allow theprobe(s) 130 to stick through the cover 200 and permit the probe(s) 130to move uninhibited by the cover 200. The cover 200 may further compriseone or more slots or openings that serve as vents 220 to permit air tocirculate in and out of the cover 200. One or more fans or pumps (notshown) may also be employed to assist in circulation of air or othergasses throughout the system.

As shown in FIGS. 6 a and 6 b, the probe mounting structure 120 maycomprise an ion source housing back plate 230 that is configured tooperably connect to an ion source housing 300. FIGS. 6 a and 6 b showalternative ion source housing back plates 230 configured for attachmentto two different ion source housing 300 configurations. The ion sourcehousing back plate 230 typically comprises at least one alignmentfeature (not shown) that is structured to align the ion source housingback plate 230 relative to the ion source housing 300 when the ionsource housing back plate 230 operably connects to the ion sourcehousing 300. Examples of alignment features include, but are not limitedto, markings, grooves, alignment holes, alignment pegs, and the like.

As shown in FIG. 7, the probe 130 comprises at least one channel 131disposed through a length of the probe 130. The probe 130 may compriseat least one sprayer needle 132 that fluidly communicates with thechannel 131. A nebulizer gas source and/or nebulizer gas sheath 133fluidly communicates with the channel. The probe 130 may also comprise athermal modulator, configured to modulate a temperature of the probe130, comprising a nebulizer gas heater 134 and a controller circuitboard 135.

As shown in FIG. 8, a first mounting 121 component is operably connectedto the probe mounting structure 120. The first mounting component isconfigured to engage at least a second mounting component (not shown)that is operably connected to an ion source housing 300 (not shown inFIG. 8) when the probe mounting structure 120 is mounted on the ionsource housing 300 (not shown in FIG. 8). The first 121 and second (notshown) mounting components may comprise hinge and/or latch components orany other means to moveably attached the mounting structure 120 to theion source housing 300.

The probe may be movably coupled to the probe mounting structure 120 viaa slide mechanism 400. The slide mechanism 400 comprises at least twoprobes 130, substantially fixedly coupled to the slide mechanism 400,and capable of sliding between a first position and a second position.The first position 130 a comprises a spray position and the secondposition comprises at least first 130 b and second 130 c rinse positionsthat are each substantially electrically isolated from the sprayposition. When a first probe 130 is in the spray position 130 a, asecond probe 130 is in the second rinse position 130 b, and when thesecond probe 130 is in the spray position 130 a, the first probe is inthe first rinse position 130 c. The slide mechanism 400 comprises aprobe support plate 420 coupled to the probe mounting structure 120 viaa linear slide 410, and the probe is mounted on the probe support plate420. The probe slide mechanism comprises a dual acting pneumaticcylinder 430 operably connected to the probe mounting structure 120 andto the probe support plate 420.

As shown in FIG. 8, an ion source housing back plate 230 comprises oneor more surfaces that define at least one spray orifice 139. The dualsprayer assembly 110 also includes at least one rinse cavity 136 that isat least partially disposed within the ion source housing back plate 230in which the rinse cavity 136 fluidly communicates with at least oneoutlet 138. The dual sprayer assembly 110 also includes at least oneprobe support structure 120 coupled to the ion source housing back plate230 via at least one linear slide 410, and at least one probe 130substantially fixedly mounted on the probe support structure 120. Theprobe conveyance mechanism 150 is operably connected to the probesupport structure 120. The probe conveyance mechanism 150 is configuredto selectively convey the probe support structure 120, such that theprobe 130 slides between the spray orifice 139 and the rinse cavity 136through the opening.

In some embodiments, the invention provides a molecular mass measurementsystem. The system includes time of flight spectrometer (TOF) 100 thatcomprises at least one ion source housing 300, and at least one dualsprayer assembly 110 operably connected to the ion source housing 300.The dual sprayer assembly 110 comprises: at least one probe mountingstructure 120; at least one probe 130 that comprises a probe opening 140that can serve as a fluid inlet and a sprayer needle 132 that can serveas a fluid outlet in which the probe opening 140 communicates with thesprayer needle 132 via a channel 131. The probe 130 is movably coupledto the probe mounting structure 120, which probe is configured todiscontinuously introduce sample aliquots into the ion source housing300; and at least one probe conveyance mechanism 150 operably connectedto the probe 130, which probe conveyance mechanism 150 is configured toconvey the probe 130 between a spray position 130 a and a rinse position130 b in which the spray position 130 a is substantially electricallyisolated from the rinse position 130 b.

B. Wide-Bore Dual Sprayer

FIG. 10 shows a representative time of flight spectrometer (TOF) 100having an exemplary wide-bore dual sprayer 510 mounted thereon. FIG. 11shows the wide-bore dual sprayer 510 and wide-bore cover 600 mounted ona TOF chamber 101, showing the chamber detached from the TOF 100. FIG.12 shows the wide-bore dual sprayer 510 separate from the TOF 100 or theTOF chamber 101. The wide-bore dual sprayer 510 comprises an ionizationprobe assembly that includes at least one wide-bore probe mountingstructure 520 and one wide-bore probe 530 (e.g. 1 probe, 2 probes, 3probes, 4 probes, 5, probes, 10 probes, etc.) that are movably coupledto the wide-bore probe mounting structure 520. Any number ofconfigurations may be used to movably couple the wide-bore probes 530 tothe wide-bore probe mounting structure 520, so long as the desiredposition and movement of the wide-bore probes 530 is provided. Thewide-bore probes 530 are configured to discontinuously introduce samplealiquots into the TOF chamber 101 (not shown in FIG. 12). Samples areintroduced into a wide-bore probe 530 via a wide-bore probe opening 540.The wide-bore probe 530 may be mounted on a probe conveyance mechanism150, operably connected to the probe. In some embodiments, the probeconveyance mechanism 150 for the wide-bore dual sprayer 510 is identicalor substantially similar to the probe conveyance mechanism 150 of anon-wide-bore dual sprayer 110 (e.g. narrow gauge dual sprayer). In someembodiments, the probe conveyance mechanism 150 for the wide-bore dualsprayer 510 is specifically designed for use with the wide-bore dualsprayer 510. The probe conveyance mechanism 150 is configured to conveythe probe between at least a first position and at least a secondposition. As shown in FIG. 12, the two probes 130 are configured topivot around an axis 160 permitting movement from the first position tothe second position. In some embodiments, the first position issubstantially electrically isolated from the second position. In someembodiments, the wide-bore dual sprayer 510 may comprise least twoindependent wide-bore probes 530 that are movably coupled to the probemounting structure 120. Each probe is movably coupled to the probemounting structure 120 via a wide-bore pivot mechanism 525. The probeconveyance mechanism 150 comprises a motor 151 operably connected to awide-bore pivot mechanisms 525 via belt drive 152.

FIGS. 13 a and 13 b show a side view of the wide-bore dual sprayer 510.In FIG. 13 a, the front-most wide-bore probe 530 is shown in the secondposition, or “spray” position. In FIG. 13 b the front-most wide-boreprobe 530 is shown in the first position, or “rinse” position. In someembodiments, a cavity is disposed in or proximal to the wide-bore probemounting structure 520 to permit movement of the wide-bore probe 530into the second position. The cavity typically comprises the secondposition. In some of these embodiments, the cavity fluidly communicateswith at least one outlet. The wide-bore probes 530 are generallyindependently movably coupled to the wide-bore probe mounting structure520. In certain embodiments, the wide-bore probe mounting structure 120includes at least one view port 123 (FIG. 8) to permit viewing of thewide-bore probes 530. The one or more view ports 123 (FIG. 8) maycomprise a glass, plastic, ceramic or other transparent material toprovide a window located on any desired region of the wide-bore mountingstructure 520. In some embodiments, a wide-bore mounting structure 520comprises a outlet and/or drain of sufficient size to prevent kick-back.

FIG. 14 shows a wide-bore dual sprayer 510 comprising a wide-bore cover600 affixed to and covering the wide-bore mounting structure 520. Insome embodiments, the wide-bore cover 600 is made of any desiredmaterial and can substantially or partially cover the wide-bore mountingstructure 520. In some embodiments, the wide-bore cover 600 is affixedto the mounting structures by screws, bolts, clamps, pins, or via anyother connection means. In some embodiments, the wide-bore cover 600comprises one or more slots or openings 210 to allow the wide-boreprobe(s) 530 to stick through the wide-bore cover 600 and permit thewide-bore probe(s) 530 to move uninhibited past the wide-bore cover 600.In some embodiments, the wide-bore cover 600 further comprises one ormore slots or openings that serve as vents 220 to permit air tocirculate in and out of the wide-bore cover 600. In some embodiments,one or more fans or pumps are employed to assist in circulation of airor other gasses throughout the system.

In some embodiments, the wide-bore probe mounting structure 520comprises an ion source housing back plate 230 that is configured tooperably connect to an ion source housing 300. FIGS. 6 a, 6 b, and 12show alternative ion source housing back plates 230 configured forattachment to different ion source housing 300 configurations. In someembodiments, a wide-bore dual sprayer utilizes an identical orsubstantially similar ion source housing back plate 230 and/or ionsource housing 300 to the non-wide-bore dual sprayer 110 (e.g. narrowgauge dual sprayer). In some embodiments, the ion source housing backplate 230 and/or ion source housing 300 specifically designed for usewith the wide-bore dual sprayer 510. The ion source housing back plate230 typically comprises at least one alignment feature that isstructured to align the ion source housing back plate 230 relative tothe ion source housing 300 when the ion source housing back plate 230operably connects to the ion source housing 300. Examples of alignmentfeatures include, but are not limited to, markings, grooves, alignmentholes, alignment pegs, and the like.

The wide-bore probe 530 comprises at least one wide-bore channel 531disposed through a length of the wide-bore probe 530 (SEE FIGS. 13A and13B). In some embodiments, the wide-bore probe 530 comprises at leastone wide-bore sprayer needle 532 that fluidly communicates with thewide-bore channel 531. A nebulizer gas source and/or nebulizer gassheath 533 fluidly communicates with the wide-bore channel 531. In someembodiments, the probe 530 further comprises a thermal modulator,configured to modulate a temperature of the wide-bore probe 530,comprising a wide-bore nebulizer gas heater 534 and a controller circuitboard 135. In some embodiments, wide-bore probe(s) 530, wide-borechannels 531, wide-bore sprayer needles 532, wide-bore nebulizer gassheaths 533, wide-bore nebulizer gas heater 534, and wide-bore probeopenings 540 are substantially similar, but generally larger indiameter, to corresponding standard, narrow-gauge, and/or non-wide-borecomponents. In some embodiments, wide-bore probe(s) 530, wide-borechannels 531, wide-bore sprayer needles 532, wide-bore nebulizer gassheaths 533, wide-bore nebulizer gas heater 534, and wide-bore probeopenings 540 are specifically designed and or tailored to a wide-boredual sprayer 510.

The wide-bore probe 530 may be movably coupled to the probe mountingstructure 520 via a slide mechanism 400. The slide mechanism 400comprises at least two wide-bore probes 530, substantially fixedlycoupled to the slide mechanism 400, and capable of sliding between afirst position 130 a and a second position 130 b (SEE FIG. 8). In someembodiments, wide-bore probes 530 of a wide-bore dual sprayer 510 areconfigured to move between spray and rinse positions in substantiallysimilar (e.g. similar, identical, etc.) fashion to non-wide-bore,standard, and/or narrow gauge probes 130. In some embodiments, awide-bore dual sprayer 510 comprises many or all of the same or similarcomponents as a non-wide-bore, standard, and/or narrow gauge dualsprayer 110 (e.g. spray orifice 139, rinse cavity 136, outlet 138, onelinear slide 410, probe conveyance mechanism 150, time of flightspectrometer (TOF) 100, etc.).

In some embodiments, the present invention provides an ion source forgenerating ions for mass spectrometric analysis. In some embodiments, anion source comprises electrospray ionization, photoionization,matrix-assisted laser desorption/ionization, chemical ionization, etc.In some embodiments, the present invention provides electrosprayionization. In some embodiments, ionization comprises forcing a liquidthrough a very small, charged (e.g. usually metal) capillary (Fenn etal. (1990) Mass Spectrometry Reviews 9 (1): 37-70., herein incorporatedby reference in its entirety). In some embodiments, a nebulizer isutilized provide an uncharged carrier gas (e.g. nitrogen, argon, etc.)to help nebulize the liquid and to help evaporate the neutral solvent inthe droplets. In some embodiments, as the solvent evaporates, theanalyte molecules are forced closer together, repel each other and breakup the droplets. In some embodiments, the process repeats until theanalyte is free of solvent and is a bare ion. In some embodiments, thepresent invention provides a nebulizer, nebulizer system, and/ornebulizer apparatus to aid in the ionization process. In someembodiments, a nebulizer and/or nebulizer system comprises a nebulizergas source, nebulizer gas lines 570, nebulizer gas-source connector 560,nebulizer gas connector 580, wide-bore nebulizer gas sheath 533 (and/ornebulizer gas sheath 133), and wide-bore nebulizer gas heater 534(and/or nebulizer gas heater 134). In some embodiments a nebulizerand/or nebulizer system further comprises a capillary, spray nozzle,insulation element, etc. In some embodiments, an insulation element,wide-bore nebulizer gas heater 534, and/or nebulizer gas heater 134 isconfigured to provide gas to a nebulizer at an appropriate temperature.In some embodiments, nebulizer gas is heated using ambient heat, heatfrom the mass spectrometer unit, and/or heat from a wide-bore nebulizergas heater 534, and/or nebulizer gas heater 134. In some embodiments,nebulizer gas lines 570 are lined or coated with one or more heatingelements. In some embodiments, heating elements lining or coating thenebulizer gas lines 570 may take any suitable form (e.g. resistancecoils, thermal tape, adhesive heater, etc.). In some embodiments, anebulizer gas heater provides a suitable level of heating to thenebulizer gas lines or other portion of the nebulizer system (e.g. 10%heating . . . 25% heating . . . 50% heating . . . 75% heating . . . 90%heating, etc.). In some embodiments, operation and heat level of anebulizer gas heater are maintained using one or more sensors (e.g.temperature sensor, function sensor, resistance sensor, etc.).

In some embodiments, a wide-bore probe mounting structure 520 (and/orprobe mounting structure 120) is provided as a removable cartridge. Insome embodiments, a wide-bore probe mounting structure 520 (and/or probemounting structure 120) is removable as a single unit. In someembodiments, a wide-bore probe mounting structure 520 (and/or probemounting structure 120) is removable in one or more pieces (e.g. 1, 2,3, 4, 5, 6, etc.). In some embodiments, the removable cartridge isspring-loaded to provide ease of removal. In some embodiments, theremovable cartridge is replaceable. In some embodiments, the presentinvention is configured to accept a number of different cartridgeconfigurations (e.g. application specific cartridge configurations).

C. Operation

In some embodiments, the present invention provides a controllerconfigured to selectively direct the ionization probe assembly 110 (orwide-bore probe assembly 510) to: (a) convey the probe from the rinseposition 130 b to the spray position 130 a; (b) spray at least onesample aliquot into the ion source housing 300 from the sample sourcewhen the probe is in the spray position 130 a; (c) convey the probe fromthe spray position 130 a to the rinse position 130 b; and (d) rinse theprobe with rinse fluid from a rinse fluid source when the probe is inthe rinse position 130 b. In some embodiments, a rinse fluid source iscontained on or within the TOF spectrometer 100, TOF chamber 101, or thedual sprayer assembly 110 (or wide-bore dual sprayer assembly 510) or islocated externally to the sprayer and spectrometer devices.

In some embodiments, the system includes at least one additional systemcomponent selected from, e.g., at least one nucleic acid amplificationcomponent; at least one sample preparation component; at least onemicroplate handling component; at least one mixing station; at least onematerial transfer component; at least one sample processing component;at least one database; and the like.

In some embodiments, the invention provides a computer program productthat includes a computer readable medium having one or more logicinstructions for directing an ionization probe assembly of a molecularmass measurement system as shown in FIGS. 9 a and b: (a) convey a firstprobe 130 (or first wide-bore probe 530) from a first rinse position 130b to a first spray position 130 a of the molecular mass measurementsystem, wherein the first rinse position 130 b and the first sprayposition 130 a are substantially electrically isolated from one another;(b) convey a second probe from a second spray position 130 c to a secondrinse position 130 d of the molecular mass measurement system, whereinthe second spray position 130 c and the second rinse position 130 d aresubstantially electrically isolated from one another; (c) spray at leasta first sample aliquot into an ion source housing 300 of the molecularmass measurement system via the first probe 130 (or first wide-boreprobe 530) when the first probe is in the first spray position 130 a;(d) rinse the second probe 130 (or second wide-bore probe 530) when thesecond probe is in the second rinse position 130 d; (e) convey the firstprobe from the first spray position 130 a to the first rinse position130 b; (f) convey the second probe from the second rinse position 130 dto the second spray position 130 c; (g) spray at least a second samplealiquot into the ion source housing of the molecular mass measurementsystem via the second probe 130 (or second wide-bore probe 530) when thesecond probe 130 (or second wide-bore probe 530) is in the second sprayposition 130 c; and, (h) rinse the first probe 130 (or first wide-boreprobe 530) when the first probe 130 (or first wide-bore probe 530) is inthe first rinse position 130 b. In some embodiments, the computerprogram product includes at least one logic instruction for directingthe dual spray assembly 110 of the molecular mass measurement system tomodulate a temperature of the first probe 130 (or first wide-bore probe530) and/or second probe 130 (or second wide-bore probe 530) using atleast one thermal modulator operably connected to the first probe and/orsecond probe. In certain embodiments, the logic instructions areconfigured to direct the dual spray assembly 110 to execute (a)substantially simultaneously with (b), (c) substantially simultaneouslywith (d), (e) substantially simultaneously with (f), and/or (g)substantially simultaneously with (h). Typically, a controller of themolecular mass measurement system comprises the logic instructions.

In another aspect, the invention provides a method of spraying samplealiquots into an ion source housing of a molecular mass measurementsystem. The method includes (a) conveying a first probe 130 (or firstwide-bore probe 530) from a first rinse position 130 b to a first sprayposition 130 a of the molecular mass measurement system in which thefirst rinse position 130 b and the first spray position 130 a aresubstantially electrically isolated from one another and wherein thefirst spray position 130 a is in fluid communication with the ion sourcehousing 300; and (b) conveying a second probe 130 (or second wide-boreprobe 530) from a second spray position 130 c to a second rinse position130 d of the molecular mass measurement system, wherein the second sprayposition 130 c and the second rinse position 130 d are substantiallyelectrically isolated from one another. The method also includes (c)spraying at least a first sample aliquot into the ion source housing 300via the first probe 130 (or first wide-bore probe 530) when the firstprobe 130 (or first wide-bore probe 530) is in the first spray position130 a; (d) rinsing the second probe 130 (or second wide-bore probe 530)when the second probe 130 (or second wide-bore probe 530) is in thesecond rinse position 130 d; and (e) conveying the first probe 130 fromthe first spray position 130 a to the first rinse position 130 b. Inaddition, the method also includes (f) conveying the second probe 130(or wide-bore probe 530) from the second rinse position 130 d to thesecond spray position 130 c in which the second spray position 130 c isin fluid communication with the ion source housing 300; (g) spraying atleast a second sample aliquot into the ion source housing 300 of themolecular mass measurement system via the second probe 130 (or secondwide-bore probe 530) when the second probe 130 (or second wide-boreprobe 530) is in the second spray position 130 c; and (h) rinsing thefirst probe 130 (or first wide-bore probe 530) when the first probe isin the first rinse position 130 b, thereby spraying the sample aliquotsinto the ion source housing 300 of the molecular mass measurementsystem. In certain embodiments, the method includes performing (a)substantially simultaneously with (b), (c) substantially simultaneouslywith (d), (e) substantially simultaneously with (f), and/or (g)substantially simultaneously with (h).

In some embodiments, the method includes modulating a temperature of thefirst probe and/or second probe using at least one thermal modulatoroperably connected to the first probe 130 (or first wide-bore probe 530)and/or second probe 130 (or second wide-bore probe 530). Typically, themethod includes ionizing the first sample aliquot and the second samplealiquot when the first sample aliquot and the second sample aliquot aresprayed into the ion source housing 300. The method also generallyincludes measuring a molecular mass of at least one component of thefirst sample aliquot and/or the second sample aliquot using themolecular mass measurement system.

In some embodiments, the component of the first sample aliquot and/orthe second sample aliquot comprises at least one nucleic acid molecule.In these embodiments, the method generally comprises determining a basecomposition of the nucleic acid molecule from the molecular mass of thenucleic acid molecule. In certain of these embodiments, the methodincludes correlating the base composition of the nucleic acid moleculewith an identity or property of the nucleic acid molecule.

In some embodiments, the present invention provides determination ofbase compositions of the amplicons are typically determined from themeasured molecular masses and correlated with an identity or source oftarget nucleic acids in the amplification reaction mixtures, such as apathogenic organism. Particular embodiments of molecular mass-baseddetection methods and other aspects that are optionally adapted for usewith the sample processing units and related aspects of the inventionare described in various patents and patent applications, including, forexample, U.S. Pat. Nos. 7,108,974; 7,217,510; 7,226,739; 7,255,992;7,312,036; and 7,339,051; and US patent publication numbers2003/0027135; 2003/0167133; 2003/0167134; 2003/0175695; 2003/0175696;2003/0175697; 2003/0187588; 2003/0187593; 2003/0190605; 2003/0225529;2003/0228571; 2004/0110169; 2004/0117129; 2004/0121309; 2004/0121310;2004/0121311; 2004/0121312; 2004/0121313; 2004/0121314; 2004/0121315;2004/0121329; 2004/0121335; 2004/0121340; 2004/0122598; 2004/0122857;2004/0161770; 2004/0185438; 2004/0202997; 2004/0209260; 2004/0219517;2004/0253583; 2004/0253619; 2005/0027459; 2005/0123952; 2005/01301962005/0142581; 2005/0164215; 2005/0266397; 2005/0270191; 2006/0014154;2006/0121520; 2006/0205040; 2006/0240412; 2006/0259249; 2006/0275749;2006/0275788; 2007/0087336; 2007/0087337; 2007/0087338 2007/0087339;2007/0087340; 2007/0087341; 2007/0184434; 2007/0218467; 2007/0218467;2007/0218489; 2007/0224614; 2007/0238116; 2007/0243544; 2007/0248969;WO2002/070664; WO2003/001976; WO2003/100035; WO2004/009849;WO2004/052175; WO2004/053076; WO2004/053141; WO2004/053164;WO2004/060278; WO2004/093644; WO 2004/101809; WO2004/111187;WO2005/023083; WO2005/023986; WO2005/024046; WO2005/033271;WO2005/036369; WO2005/086634; WO2005/089128; WO2005/091971;WO2005/092059; WO2005/094421; WO2005/098047; WO2005/116263;WO2005/117270; WO2006/019784; WO2006/034294; WO2006/071241;WO2006/094238; WO2006/116127; WO2006/135400; WO2007/014045;WO2007/047778; WO2007/086904; and WO2007/100397; WO2007/118222, whichare each incorporated by reference as if fully set forth herein.

Exemplary molecular mass-based analytical methods and other aspects ofuse in the sample processing units and systems described herein are alsodescribed in, e.g., Ecker et al. (2005) “The Microbial Rosetta StoneDatabase: A compilation of global and emerging infectious microorganismsand bioterrorist threat agents” BMC Microbiology 5(1):19; Ecker et al.(2006) “The Ibis T5000 Universal Biosensor: An Automated Platform forPathogen Identification and Strain Typing” JALA 6(10:341-351.; Ecker etal. (2006) “Identification of Acinetobacter species and genotyping ofAcinetobacter baumannii by multilocus PCR and mass spectrometry” J ClinMicrobiol. 44(8):2921-32.; Ecker et al. (2005) “Rapid identification andstrain-typing of respiratory pathogens for epidemic surveillance” ProcNatl Acad Sci USA. 102(22):8012-7; Hannis et al. (2008) “High-resolutiongenotyping of Campylobacter species by use of PCR and high-throughputmass spectrometry” J Clin Microbiol. 46(4):1220-5; Blyn et al. (2008)“Rapid detection and molecular serotyping of adenovirus by use of PCRfollowed by electrospray ionization mass spectrometry” J Clin Microbiol.46(2):644-51; Sampath et al. (2007) “Global surveillance of emergingInfluenza virus genotypes by mass spectrometry” PLoS ONE 2(5):e489;Sampath et al. (2007) “Rapid identification of emerging infectiousagents using PCR and electrospray ionization mass spectrometry” Ann N YAcad Sci. 1102:109-20; Hall et al. (2005) “Base composition analysis ofhuman mitochondrial DNA using electrospray ionization mass spectrometry:a novel tool for the identification and differentiation of humans” AnalBiochem. 344(1):53-69; Hofstadler et al. (2003) “A highly efficient andautomated method of purifying and desalting PCR products for analysis byelectrospray ionization mass spectrometry” Anal Biochem. 316:50-57;Hofstadler et al. (2006) “Selective ion filtering by digitalthresholding: A method to unwind complex ESI-mass spectra and eliminatesignals from low molecular weight chemical noise” Anal Chem.78(2):372-378.; and Hofstadler et al. (2005) “TIGER: The UniversalBiosensor” Int J Mass Spectrom. 242(1):23-41, which are eachincorporated by reference.

In addition to the molecular mass and base composition analyses referredto above, essentially any other nucleic acid amplification technologicalprocess is also optionally adapted for use in the systems of theinvention. Other exemplary uses of the systems and other aspects of theinvention include numerous biochemical assays, cell culture purificationsteps, and chemical synthesis, among many others. Many of these as wellas other exemplary applications of use in the systems of the inventionare also described in, e.g., Current Protocols in Molecular Biology,Volumes I, II, and III, 1997 (F. M. Ausubel ed.); Perbal, 1984, APractical Guide to Molecular Cloning; the series, Methods in Enzymology(Academic Press, Inc.); Sambrook et al., 2001, Molecular Cloning: ALaboratory Manual, Third Edition, Cold Spring Harbor Laboratory Press,Cold Spring Harbor, N.Y.; Oligonucleotide Synthesis, 1984 (M. L. Gaited.); Nucleic Acid Hybridization, 1985, (Hames and Higgins);Transcription and Translation, 1984 (Hames and Higgins eds.); AnimalCell Culture, 1986 (R. I. Freshney ed.); Berger and Kimmel, Guide toMolecular Cloning Techniques, Methods in Enzymology volume 152 AcademicPress, Inc., San Diego, Calif. (Berger), DNA Cloning: A PracticalApproach, Volumes I and II, 1985 (D. N. Glover ed.); Immobilized Cellsand Enzymes, 1986 (IRL Press); Gene Transfer Vectors for MammalianCells, 1987 (J. H. Miller and M. P. Calos eds., Cold Spring HarborLaboratory); and Methods in Enzymology Vol. 154 and Vol. 155 (Wu andGrossman, and Wu, eds., respectively), which are each incorporated byreference.

In some embodiments, one or more controllers and/or computers may beoperably attached to devices of the present invention to selectconditions under which molecular mass measurement are made using adevice of the present invention. The controllers and/or computersconfigured to operate with devices described herein are generallyconfigured to effect, e.g., temperature, sample volume, number of runs,sample switching, probe rinsing conditions, spray conditions, etc.Controllers and/or computers are typically operably connected to one ormore system components, such as motors (e.g., via motor drives), thermalmodulating components, detectors, motion sensors, fluidic handlingcomponents, robotic translocation devices, or the like, to controloperation of these components. Controllers and/or other systemcomponents is/are generally coupled to an appropriately programmedprocessor, computer, digital device, or other logic device orinformation appliance (e.g., including an analog to digital or digitalto analog converter as needed), which functions to instruct theoperation of these instruments in accordance with preprogrammed or userinput instructions (e.g., mixing mode selection, fluid volumes to beconveyed, etc.), receive data and information from these instruments,and interpret, manipulate and report this information to the user.

A controller or computer optionally includes a monitor which is often acathode ray tube (“CRT”) display, a flat panel display (e.g., activematrix liquid crystal display, liquid crystal display, etc.), or others.Computer circuitry is often placed in a box, which includes numerousintegrated circuit chips, such as a microprocessor, memory, interfacecircuits, and others. The box also optionally includes a hard diskdrive, a floppy disk drive, a high capacity removable drive such as awriteable CD-ROM, and other common peripheral elements. Inputtingdevices such as a keyboard or mouse optionally provide for input from auser.

In some embodiments, a computer includes appropriate software forreceiving user instructions, either in the form of user input into a setof parameter fields, e.g., in the form of preprogrammed instructions,e.g., preprogrammed for a variety of different specific operations. Thesoftware then converts these instructions to appropriate language forinstructing the operation of one or more controllers to carry out thedesired operation, e.g., rinsing probe, switching fluids, taking massmeasurements, or the like. The computer then receives the data from,e.g., sensors/detectors included within the system, and interprets thedata, either provides it in a user understood format, or uses that datato initiate further controller instructions, in accordance with theprogramming.

More specifically, the software utilized to control the operation of thedevices and systems of the invention typically includes logicinstructions that selectively direct, e.g., motors to more probes, rateof probe movement, rate of sampling, data acquisition, and the like. Thelogic instructions of the software are typically embodied on a computerreadable medium, such as a CD-ROM, a floppy disk, a tape, a flash memorydevice or component, a system memory device or component, a hard drive,a data signal embodied in a carrier wave, and/or the like. Othercomputer readable media are known to persons of skill in the art. Insome embodiments, the logic instructions are embodied in read-onlymemory (ROM) in a computer chip present in one or more systemcomponents, without the use of personal computers.

The computer can be, e.g., a PC (Intel x86 or Pentium chip-compatibleDOS™, OS2™, WINDOWS™, WINDOWS NT™, WINDOWS98™, WINDOWS2000™, WINDOWSXP™, WINDOWS Vista™, LINUX-based machine, a MACINTOSH™, Power PC, or aUNIX-based (e.g., SUN™ work station) machine) or other commoncommercially available computer which is known to one of skill. Standarddesktop applications such as word processing software (e.g., MicrosoftWord™ or Corel WordPerfect™) and database software (e.g., spreadsheetsoftware such as Microsoft Excel™, Corel Quattro Pro™, or databaseprograms such as Microsoft Access™ or Paradox™) can be adapted to thepresent invention. Software for performing, e.g., sample processing unitcontainer rotation, material conveyance to and/or from sample processingunit containers, mixing process monitoring, assay detection, and datadeconvolution is optionally constructed by one of skill using a standardprogramming language such as Visual basic, C, C++, Fortran, Basic, Java,or the like.

Devices and systems of the invention may also include at least onerobotic translocation or gripping component that is structured to gripand translocate fluids, containers, or other components betweencomponents of the devices or systems and/or between the devices orsystems and other locations (e.g., other work stations, etc.). A varietyof available robotic elements (robotic arms, movable platforms, etc.)can be used or modified for use with these systems, which roboticelements are typically operably connected to controllers that controltheir movement and other functions.

Devices, systems, components thereof, and station or system componentsof the present invention are optionally formed by various fabricationtechniques or combinations of such techniques including, e.g.,machining, embossing, extrusion, stamping, engraving, injection molding,cast molding, etching (e.g., electrochemical etching, etc.), or othertechniques. These and other suitable fabrication techniques aregenerally known in the art and described in, e.g., Molinari et al.(Eds.), Metal Cutting and High Speed Machining, Kluwer AcademicPublishers (2002), Altintas, Manufacturing Automation: Metal CuttingMechanics, Machine Tool Vibrations, and CNC Design, Cambridge UniversityPress (2000), Stephenson et al., Metal Cutting Theory and Practice,Marcel Dekker (1997), Fundamentals of Injection Molding, W. J. T.Associates (2000), Whelan, Injection Molding of ThermoplasticsMaterials, Vol. 2, Chapman & Hall (1991), Rosato, Injection MoldingHandbook, 3^(rd) Ed., Kluwer Academic Publishers (2000), Fisher,Extrusion of Plastics, Halsted Press (1976), and Chung, Extrusion ofPolymers: Theory and Practice, Hanser-Gardner Publications (2000), whichare each incorporated by reference. Exemplary materials optionally usedto fabricate devices or systems of the present invention, or componentsthereof include metal (e.g., steel, aluminum, etc.), glass,polymethylmethacrylate, polyethylene, polydimethylsiloxane,polyetheretherketone, polytetrafluoroethylene, polystyrene,polyvinylchloride, polypropylene, polysulfone, polymethylpentene, andpolycarbonate, among many others. In certain embodiments, followingfabrication, system components are optionally further processed, e.g.,by coating surfaces with a hydrophilic coating, a hydrophobic coating(e.g., a Xylan 1010DF/870 Black coating available from WhitfordCorporation (West Chester, Pa.), etc.), or the like, e.g., to preventinteractions between component surfaces and reagents, samples, or thelike.

In some embodiments, a wide-bore dual sprayer 510 is operationallysimilar to a non-wide-bore, standard, and/or narrow-gauge dual sprayer110. In some embodiments, dual sprayers 110 a wide-bore dual sprayers510 are configured to accommodate cartridge assemblies of commercialinstruments. In some embodiments, dual sprayers 110 a wide-bore dualsprayers 510 comprise a spring-loaded portion (e.g. comprising wide-boreprobes, wide-bore pivot mechanism 525, and related structures). In someembodiments, one or more portions, elements, and/or components areconfigured to be readily removable from the dual sprayer 110 a wide-boredual sprayer 510 (e.g. for easy replacement). In some embodiments, awide-bore dual sprayer 510 comprises a drain hole which is larger thanthat of a non-wide-bore, standard, and/or narrow-gauge dual sprayer 110(e.g. larger drain hole prevent gas from kicking back up).

While the foregoing invention has been described in some detail forpurposes of clarity and understanding, it will be clear to one skilledin the art from a reading of this disclosure that various changes inform and detail can be made without departing from the true scope of theinvention. For example, all the techniques and apparatus described abovecan be used in various combinations. All publications, patents, patentapplications, and/or other documents cited in this application areincorporated by reference in their entirety for all purposes to the sameextent as if each individual publication, patent, patent application,and/or other document were individually indicated to be incorporated byreference for all purposes.

1. An ionization probe assembly, comprising: at least one probe mountingstructure; at least one probe that is movably coupled to the probemounting structure, which probe is configured to discontinuouslyintroduce sample aliquots into an ion source housing; and, at least oneprobe conveyance mechanism operably connected to the probe, which probeconveyance mechanism is configured to convey the probe between at leasta first position and at least a second position, wherein the firstposition is substantially electrically isolated from the secondposition.
 2. The ionization probe assembly of claim 1, wherein the probemounting structure comprises at least one view port.
 3. The ionizationprobe assembly of claim 1, comprising at least one cover operablyconnected to the probe mounting structure.
 4. An electrospray ion sourcehousing comprising the ionization probe assembly of claim
 1. 5. A massspectrometer comprising the electrospray ion source housing of claim 4.6. The ionization probe assembly of claim 1, wherein the probe mountingstructure comprises an ion source housing back plate that is configuredto operably connect to an ion source housing.
 7. The ionization probeassembly of claim 6, wherein the ion source housing back plate comprisesat least one alignment feature that is structured to align the ionsource housing back plate relative to the ion source housing when theion source housing back plate operably connects to the ion sourcehousing.
 8. The ionization probe assembly of claim 1, wherein at leastone channel is disposed through a length of the probe.
 9. The ionizationprobe assembly of claim 8, wherein the probe comprises at least onesprayer needle that fluidly communicates with the channel.
 10. Theionization probe assembly of claim 8, wherein at least one nebulizer gassource and/or nebulizer gas sheath fluidly communicates with thechannel.
 11. The ionization probe assembly of claim 1, comprising atleast one thermal modulator operably connected to the probe, whichthermal modulator is configured to modulate a temperature of the probe.12. The ionization probe assembly of claim 11, wherein the thermalmodulator comprises a nebulizer gas heater.
 13. The ionization probeassembly of claim 11, comprising at least one controller circuit boardoperably connected to the thermal modulator.
 14. The ionization probeassembly of claim 1, comprising at least a first mounting componentoperably connected to the probe mounting structure, which first mountingcomponent is configured to engage at least a second mounting componentthat is operably connected to an ion source housing when the probemounting structure is mounted on the ion source housing.
 15. Theionization probe assembly of claim 14, wherein the first and secondmounting components comprise hinge and/or latch components.
 16. Theionization probe assembly of claim 1, comprising at least one cavitydisposed in or proximal to the probe mounting structure, which cavitycomprises the second position.
 17. The ionization probe assembly ofclaim 16, wherein the cavity fluidly communicates with at least oneoutlet.
 18. The ionization probe assembly of claim 1, comprising atleast two probes that are each movably coupled to the probe mountingstructure.
 19. The ionization probe assembly of claim 18, wherein theprobes are independently movably coupled to the probe mountingstructure.
 20. The ionization probe assembly of claim 1, wherein theprobe mounting structure comprises an ion source housing.
 21. Theionization probe assembly of claim 20, wherein the ion source housingcomprises at least one view port.
 22. The ionization probe assembly ofclaim 1, comprising at least two probes independently movably coupled tothe probe mounting structure.
 23. The ionization probe assembly of claim22, wherein each probe is movably coupled to the probe mountingstructure via a pivot mechanism.
 24. The ionization probe assembly ofclaim 23, wherein the probe conveyance mechanism comprises at least onemotor operably connected to at least one of the pivot mechanisms via apulley and belt drive assembly.
 25. The ionization probe assembly ofclaim 22, wherein each probe is configured to move between a sprayposition and a rinse position, wherein the spray position issubstantially electrically isolated from the rinse position.
 26. Theionization probe assembly of claim 25, comprising at least one cavitydisposed in or proximal to the probe mounting structure, which cavitycomprises at least one of the rinse positions.
 27. The ionization probeassembly of claim 26, wherein the cavity fluidly communicates with atleast one outlet.
 28. The ionization probe assembly of claim 1, whereinthe probe is movably coupled to the probe mounting structure via a slidemechanism.
 29. The ionization probe assembly of claim 28, wherein theslide mechanism comprises at least two probes.
 30. The ionization probeassembly of claim 29, wherein the probes are substantially fixedlycoupled to the slide mechanism.
 31. The ionization probe assembly ofclaim 29, wherein the first position comprises a spray position andwherein the second position comprises at least first and second rinsepositions that are each substantially electrically isolated from thespray position.
 32. The ionization probe assembly of claim 31, whereinwhen a first probe is in the spray position, a second probe is in thesecond rinse position, and when the second probe is in the sprayposition, the first probe is in the first rinse position.
 33. Theionization probe assembly of claim 28, wherein the slide mechanismcomprises a probe support plate coupled to the probe mounting structurevia a linear slide, and wherein the probe is mounted on the probesupport plate.
 34. The ionization probe assembly of claim 33, whereinthe probe conveyance mechanism comprises a dual acting pneumaticcylinder operably connected to the probe mounting structure and to theprobe support plate.
 35. The ionization probe assembly of claim 1,wherein said at least one probe comprises at least one wide-bore probe.36. The ionization probe assembly of claim 1, wherein said probemounting structure comprises a removable cartridge.
 37. The ionizationprobe assembly of claim 36, wherein said removable cartridge isspring-loaded.
 38. The ionization probe assembly of claim 36, whereinsaid probe mounting structure is configured to accept removablecartridges from a variety of commercial instruments.
 39. The ionizationprobe assembly of claim 1, further comprising one or more nebulizer gaslines configured to deliver gas from a nebulizer gas source to said atleast one probe.
 40. The ionization probe assembly of claim 39, whereinsaid one or more nebulizer gas lines comprise a thermal modulator toheat gas within said one or more nebulizer gas lines.
 41. An ionizationprobe assembly, comprising: at least one ion source housing back platethat comprises one or more surfaces that define at least one sprayorifice, which ion source housing back plate is configured to operablyconnect to an ion source housing; at least one rinse cavity that is atleast partially disposed within the ion source housing back plate,wherein the rinse cavity communicates with the spray orifice via atleast one opening; at least one probe support structure coupled to theion source housing back plate via at least one linear slide; at leastone probe substantially fixedly mounted on the probe support structure;and, at least one probe conveyance mechanism operably connected to theprobe support structure, which probe conveyance mechanism is configuredto selectively convey the probe support structure such that the probeslides between the spray orifice and the rinse cavity through theopening.
 42. The ionization probe assembly of claim 41, wherein therinse cavity fluidly communicates with at least one outlet.
 43. Anionization probe assembly, comprising: at least one ion source housingback plate that comprises one or more surfaces that define at least onespray orifice, which ion source housing back plate is configured tooperably connect to an ion source housing; at least one rinse cavitythat is at least partially disposed within the ion source housing backplate, wherein the rinse cavity communicates with the spray orifice viaat least one opening; at least one probe movably coupled to the ionsource housing back plate via at least one pivot mechanism; and, atleast one probe conveyance mechanism that comprises at least one motoroperably connected to the pivot mechanism via a pulley and belt driveassembly, which probe conveyance mechanism is configured to selectivelyconvey the probe between the spray orifice and the rinse cavity throughthe opening.
 44. A molecular mass measurement system, comprising: atleast one mass spectrometer that comprises at least one ion sourcehousing; at least one ionization probe assembly operably connected tothe ion source housing, which ionization probe assembly comprises: atleast one probe mounting structure; at least one probe that comprises atleast one inlet and at least one outlet, wherein the inlet fluidlycommunicates with the outlet, wherein the probe is movably coupled tothe probe mounting structure, which probe is configured todiscontinuously introduce sample aliquots into the ion source housing;and at least one probe conveyance mechanism operably connected to theprobe, which probe conveyance mechanism is configured to convey theprobe between a spray position and a rinse position, wherein the sprayposition is substantially electrically isolated from the rinse position;at least one sample source in fluid communication with the inlet of theprobe; at least one rinse fluid source in fluid communication with theinlet of the probe; and, at least one controller operably connected atleast to the ionization probe assembly, which controller is configuredto selectively direct the ionization probe assembly to: (a) convey theprobe from the rinse position to the spray position; (b) spray at leastone sample aliquot into the ion source housing from the sample sourcewhen the probe is in the spray position; (c) convey the probe from thespray position to the rinse position; and (d) rinse the probe with rinsefluid from the rinse fluid source when the probe is in the rinseposition.
 45. The system of claim 44, comprising at least one additionalsystem component selected from the group consisting of: at least onenucleic acid amplification component; at least one sample preparationcomponent; at least one microplate handling component; at least onemixing station; at least one material transfer component; at least onesample processing component; and at least one database.
 46. A computerprogram product, comprising a computer readable medium having one ormore logic instructions for directing an ionization probe assembly of amolecular mass measurement system to: (a) convey a first probe from afirst rinse position to a first spray position of the molecular massmeasurement system, wherein the first rinse position and the first sprayposition are substantially electrically isolated from one another; (b)convey a second probe from a second spray position to a second rinseposition of the molecular mass measurement system, wherein the secondspray position and the second rinse position are substantiallyelectrically isolated from one another; (c) spray at least a firstsample aliquot into an ion source housing of the molecular massmeasurement system via the first probe when the first probe is in thefirst spray position; (d) rinse the second probe when the second probeis in the second rinse position; (e) convey the first probe from thefirst spray position to the first rinse position; (f) convey the secondprobe from the second rinse position to the second spray position; (g)spray at least a second sample aliquot into the ion source housing ofthe molecular mass measurement system via the second probe when thesecond probe is in the second spray position; and, (h) rinse the firstprobe when the first probe is in the first rinse position.
 47. Thecomputer program product of claim 46, comprising at least one logicinstruction for directing the ionization probe assembly of the molecularmass measurement system to modulate a temperature of the first probeand/or second probe using at least one thermal modulator operablyconnected to the first probe and/or second probe.
 48. The computerprogram product of claim 46, wherein the logic instructions areconfigured to direct the ionization probe assembly to execute (a)substantially simultaneously with (b), (c) substantially simultaneouslywith (d), (e) substantially simultaneously with (f), and/or (g)substantially simultaneously with (h).
 49. The computer program productof claim 46, wherein a controller of the molecular mass measurementsystem comprises the logic instructions.
 50. A method of spraying samplealiquots into an ion source housing of a molecular mass measurementsystem, the method comprising: (a) conveying a first probe from a firstrinse position to a first spray position of the molecular massmeasurement system, wherein the first rinse position and the first sprayposition are substantially electrically isolated from one another andwherein the first spray position is in fluid communication with the ionsource housing; (b) conveying a second probe from a second sprayposition to a second rinse position of the molecular mass measurementsystem, wherein the second spray position and the second rinse positionare substantially electrically isolated from one another; (c) sprayingat least a first sample aliquot into the ion source housing via thefirst probe when the first probe is in the first spray position; (d)rinsing the second probe when the second probe is in the second rinseposition; (e) conveying the first probe from the first spray position tothe first rinse position; (f) conveying the second probe from the secondrinse position to the second spray position, wherein the second sprayposition is in fluid communication with the ion source housing; (g)spraying at least a second sample aliquot into the ion source housing ofthe molecular mass measurement system via the second probe when thesecond probe is in the second spray position; and, (h) rinsing the firstprobe when the first probe is in the first rinse position, therebyspraying the sample aliquots into the ion source housing of themolecular mass measurement system.
 51. The method of claim 50,comprising performing (a) substantially simultaneously with (b), (c)substantially simultaneously with (d), (e) substantially simultaneouslywith (f), and/or (g) substantially simultaneously with (h).
 52. Themethod of claim 50, comprising modulating a temperature of the firstprobe and/or second probe using at least one thermal modulator operablyconnected to the first probe and/or second probe.
 53. The method ofclaim 50, comprising ionizing the first sample aliquot and the secondsample aliquot when the first sample aliquot and the second samplealiquot are sprayed into the ion source housing.
 54. The method of claim50, comprising measuring a molecular mass of at least one component ofthe first sample aliquot and/or the second sample aliquot using themolecular mass measurement system.
 55. The method of claim 50, whereinthe component of the first sample aliquot and/or the second samplealiquot comprises at least one nucleic acid molecule and wherein themethod comprises determining a base composition of the nucleic acidmolecule from the molecular mass of the nucleic acid molecule.
 56. Themethod of claim 50, comprising correlating the base composition of thenucleic acid molecule with an identity or property of the nucleic acidmolecule.